HIV-I infected long-term non progressors (LT-NP), characterized by normal CD4 counts and no HIV related symptoms form least 5-I0 years post infection, represent less than 5% of HIV-I infected patients. However, a significant number of LT-NP progress to AIDS early on, which suggests that in addition to HIV-I, other factors may play a major role in disease progression. For several years we have investigated the premise that drugs of abuse suppress various immune responses that protect the host from HIV infections and progression to AIDS. However ,the role of opioids in the progression of HIV disease in LT-NP has not been clearly elucidated. Among the early efforts, we were also the first to report that intravenous drug users, including opioid users, manifest low NK activity compared to matched control subjects. We further demonstrated that in vivo stereotaxic injection of HIV proteins plus excitatory amino acid agonists into the dorsal hippocampus of neonatal rat brains causes both gross and microscopic neuropathology. These interests merged in a series of preliminary studies demonstrating that opioids potentiate various neuro-immunopathogenic mechanisms mediated by HIV proteins. Thus, we hypothesize that: opioids are cofactors in the pathogenesis of HIV infection in LT-NP acting in svnergy with certain HIV proteins to affect the immune and central nervous systems of the infected host. Several experimental approaches will be used to determine the molecular mechanisms underlying the opioid-mediated neuro-immune-dysfunctions in LT-NP compared to normal progressors (NP) and controls. Total PBMC, cytotoxic T lymphocytes (CTL), dendritic and monocyte subsets from opioid using and non using LT-NP, NP, seronegative opioid users and normal donors will be cultured with HIV-1 (gp-120/tat) or morphine or HIV proteins plus morphine to look for modulation of various immune responses including dysregulation of CTL, dendritic cell functions, cytokines/chcmokines, IL-16, upregulation of HIV entry co-receptors, neurotoxins (matrix mcmlloproteasc-2 and-9,nitric oxide, quinolinic acid)TGF-beta I, apoptosis, STAT-4/6 and CD45 tyrosine phosphatase. Data will be stratified on the basis of HIV disease status, CD4 count, HIV viral RNA copy numbers and opioid use. Further, human brain microvessel endothelial cells, several human CNS cell lines and primary astrocyte and neural progenitor cultures will be used to study the effects of morphine/HIV proteins on adhesion molecules and neurotoxins which help in the transmigration of infected monocytes into the brain. Neurotoxicity will be correlated with the neurotoxin production by treated CNS cells and endothelial ceils. Our preliminary studies show that LT-NP demonstrate that increased IL-16, increased CTL activity and decreased TGF-beta1comparedtoNP. Further studies will elucidate the molecular mechanisms underlying the immune- and neuro-pathogenic effects of opioid in the natural history of HIV disease progression in LT-NP and may ultimately help to define effective therapeutic mechanisms to prolong the disease free state in LT-NP.